MXPA00009494A - Conformationally constrained amino acid compounds having affinity for the alpha2delta subunit of a calcium channel - Google Patents

Abstract

Novel substituted amino acids of formulae (I) to (VIII) are disclosed and are useful as agents in the treatment of epilepsy, faintness attacks,hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, and neuropathological disorders. Processes for the preparation and intermediates useful in the preparation are also disclosed.

Description

CONFORMACIONALLY RESTRICTED AMINO ACID COMPOUNDS THAT HAVE AFFINITY FOR THE ALFA2DELTA SUBUNITY OF A CALCIUM CHANNEL BACKGROUND OF THE INVENTION Compounds of the formula wherein Rf is hydrogen or a lower alkyl radical and n is 4, 5 or 6 as described in U.S. Patent Number 4,024,175 and its U.S. Patent Number 4,087,544. The uses described are: protective effect against numbness induced by thiosemicarbazide, protective action against numbness caused by cardiazol, brain diseases, epilepsy, mental lacunae, hypokinesia and cranial traumas and improvement of brain functions. The compounds are useful in geriatric patients. The patents are incorporated herein by reference.

SUMMARY OF THE INVENTION Compounds, prodrugs and pharmaceutically acceptable salts are useful for various diseases. The diseases include: epilepsy, mental lacunae, hypokinesia, cranial diseases, neurodegenerative diseases, depression, anxiety, panic, pain and neuropathological diseases.

The compounds are those of the formula II m (VII) (HIV) or a pharmaceutically acceptable salt or a prodrug thereof wherein R1 to Rio are each independently selected from hydrogen or a long or branched chain alkyl of 1 to 6 carbon atoms, benzyl or phenyl; m is an integer from 0 to 3; n is an integer from 1 to 2; or is an integer from 0 to 3; p is an integer from 1 to 2; q is an integer from 0 to 2; r is an integer from 1 to 2; s is an integer from 1 to 3; t is an integer from 0 to 2 and u is an integer from 0 to 1. The novel intermediates useful in the preparation of the final compounds are, for example: 2-Benzyl-2-aza-spiro acid dimethyl ester hydrochloride [4.5] decane-4,4-dicarboxylic; 2-Aza-spiro [4.5] decane-4,4-dicarboxylic acid dimethyl ester hydrochloride; Ester tert-butyl 1-Benzyloxymethyl-2-aza-spiro [3.5] nonane-2-carboxylic acid; Ester tert-butyl 1-Hydroxymethyl-2-aza-spiro [3.5] nonane-2-carboxylic acid; 2-Aza-spiro [3.5] nonane-1,2-dicarboxylic acid 2-tert-butyl ester; Ester tert-butyl of [3aS- (3a7aa)] - 7a-tert-Butoxycarbonylmethyl-1-oxo-octahydro-isoindol-2-carboxylic acid ester and tert-butyl acid of [3aS- (a7aa)] - 3a-tert- Butoxycarbonylmethyl-octahydro-isoindol-2-carboxylic acid.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention and their pharmaceutically acceptable salts and prodrugs are as defined by Formula I to VIII above. Preferred compounds are those of Formula I above. Especially preferred are those of Formula I wherein R a to R-io is hydrogen; m is from 0 to 3 and n is 1 or 2. More specifically are those compounds selected from: (±) -2-Aza-spiro [3.5] nonane-1-carboxylic acid hydrochloride (±) -2-Aza hydrochloride -spiro [4.5] decane-4-carboxylic acid (R) -2-Aza-spiro [4.5] decane-4-carboxylic acid hydrochloride; (S) -2-Aza-spiro [4.5] decane-4-carboxylic acid and (R) -2-Aza-spiro [4.5] decane-4-carboxylic acid hydrochloride. Other preferred components are those of the above Formula II. Especially preferred are those of Formula II wherein R-a Rio is hydrogen or is from 0 to 3 and p is 1 to 2. Other preferred compounds are those of Formula III above, wherein Ri to R10 is hydrogen, q is 0 to 2 and r is 1 to 2. The (±) - [3aS- (3a, 7aa)] - (Octahydro-isoindol-3a-yl) -acetic acid trifluoroacetate is especially preferred. Also especially preferred are the compounds selected from: 7-Methyl-2-aza-spiro [4.4] nonane-4-carboxylic acid; [4a5β (R *)] 7-Methyl-2-aza-spiro [4.5] decane-4-carboxylic acid; Acid [4a, 5a (S *)] 7-Methyl-2-aza-spiro [4.5] decane-4-carboxylic acid; Acid [4a, 5a (R *)] 7-Methyl-2-aza-spiro [4.5] decane-4-carboxylic acid; [4a, 5β (S *)] 7-Methyl-2-aza-spiro [4.5] decane-4-carboxylic acid; 7,8-Dimethyl-2-aza-spiro [4.4] nonane-4-carboxylic acid; 7-Methyl-2-aza-spiro [4.5] decane-4-carboxylic acid; 7,9-Dimethyl-2-aza-spiro [4.5] decane-4-carboxylic acid; Spiro [bicyclo [3.3.1] nonane-9,3'-pyrrolidine] -4-'carboxylic acid; Spiro [pyrrolidine-3,2'-tricyclo [3.3.1.13,7] decane] -4-carboxylic acid; 3-Amino-6-methyl-spiro [3.5] nonane-1-carboxylic acid; 3-Amino-6,8-dimethyl-spiro [3.5] nonane-1-carboxylic acid; 4-Amino-7-methyl-spiro [4.5] decane-1-carboxylic acid; 4-Amino-7,9-dimethyl-spiro [4.5] decane-1-carboxylic acid; 3-Amino-6-methyl-spiro [3,4] octane-1-carboxylic acid 3-Amino-6,7-dimethyl-spiro [3,4] octane-1-carboxylic acid; 4-Amino-7-methyl-spiro [4.4] nonane-1-carboxylic acid and 4-Amino-7,8-dimethyl-spiro [4.4] nonane-1-carboxylic acid. Pharmaceutical compositions comprising a therapeutically effective amount of a compound of the above Formulas I-Vlli are included in the present invention. The methods of using the compounds of the invention as agents for treating epilepsy, mental lacunae, hypokinesia, cranial diseases, neurodegenerative diseases, depression, anxiety, panic, pain and neuropathological diseases are part of the invention. The term "alkyl" is a long or branched chain group of 1 to 6 carbon atoms including but not limited to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl and n-hexyl. Preferred groups are methyl and tert-butyl. The benzyl and phenyl groups can be substituted or unsubstituted by 1 to 3 substituents selected from halogen, alkyl, alkoxy, hydroxy, carboxy, carboalkoxy, trifluoromethyl and nitro.

Halogens include fluorine, bromine, chlorine and iodine. Since the amino acids are amphoteric pharmacologically compatible salts when R is hydrogen they can be salts of organic or inorganic acids, for example, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, oxalic acid, lactic acid, citric acid, malic acid, acid salicylic acid, malonic acid, maleic acid, succinic acid and ascorbic acid. They are formed starting from the corresponding hydroxides or carbonates, the salts with alkali metals or other alkaline earth metals, for example, sodium, potassium, magnesium or calcium. Salts with quaternary ammonium ions can also be prepared with, for example, the tetramethyl ammonium ion. The prodrugs of compounds I-VI 11 are included in the scope of the present invention. The lactic and aminoacyl-glycolic esters are known as amino acid prodrugs (Wermuth O G., Chemistry and Industry, 1980: 433-435). The carbonyl group of the amino acids can be esterified by known means. Prodrugs and mild drugs are known in the art (Palomino E., Drugs of the Future, 1990; 15 (4): 361-368). The last two citations are incorporated in this document as a reference.

The effectiveness of an orally administered drug is dependent on the efficient transport of the drug through the mucosal epithelium and its stability in the entero-hepatic circulation. Drugs that are effective after parenteral administration but less effective orally or whose plasma half-life is considered too short may be chemically modified in a prodrug form. A prodrug is a drug that has been chemically modified and may be biologically inactive at its site of action, but which can be degraded or modified by one or more enzymatic processes or other processes in vivo to the bioactive form of origin.

This drug chemically modified or prodigal, must have a pharmacokinetic profile different from the one of origin, allowing its easy absorption through the mucosal epithelium, better saline formulation and / or solubility, improved systemic stability (for an increase in the half-life of the plasma, for example). These chemical modifications can be 1) derivatives of the ester or amide that can be penetrated by, for example, esterases or lipases. For ester derivatives, the ester is derived from the carboxylic acid moiety of the drug molecule by known means. For the amide derivatives, the amide can be derived from the carboxylic acid portion or the amine portion of the drug molecule by known means. 2) peptides that can be recognized by non-specific or specific proteinases. A peptide can be coupled to the drug molecule via the formation of the amide bond with the carboxylic acid or amine moiety of the drug molecule by known means. 3) Derivatives that accumulate in an action site through the selection of the membrane in a prodrug form or a modified prodrug form, 4) Any combination of 1 to 3. Current research in animal experiments has shown that absorption oral administration of certain drugs can be increased by the preparation of "soft" quaternary salts. Quaternary salt is called a "soft" quaternary salt because unlike normal quaternary salts, for example R-N + (CH3) 3, it can release the active drug in hydrolysis. The "soft" quaternary salts have useful physical properties compared to the basic drug or its salts. The solubility in water may be increased compared to other salts such as the hydrochloride salt, but more importantly, there may be an increased absorption of the drug by the intestine. The increased absorption is probably due to the fact that the "soft" quaternary salt has surfactant properties and is capable of forming non-ionized ion pairs and micelles with bile acids, etc., which are able to penetrate the intestinal epithelium more effectively. The prodrug, after absorption, hydrolyzes rapidly with the release of the active origin drug. Certain compounds of the present invention can exist in unsolvated forms as well as in solvated forms, including hydrated forms. In general, solvated forms including hydrated forms are equivalent to unsolvated forms and are included within the scope of the present invention. Certain compounds of the present invention possess one or more chiral centers and each center may exist in the R (D) or S (L) configuration. The present invention includes all epimeric and enantiomeric forms as well as appropriate mixtures thereof. For example, the compound of Example 1 is a mixture of all four possible stereoisomers. The compound of Example 6 is one of the isomers. The configuration of the carbon centers of the cyclohexane ring can be R or S in these compounds where a configuration can be defined. The radioligand binding test was used using gabapentin [3H] and the a2d subunit derived from porcine brain tissue (Gee N.S., Brown J.P., Dissanayake V.U.K., Offord J., Thurlow R.; Woodruff I.N., "The Novel Anticonvulsant Drug, Gabapentin, Binds to the a2d Subunit of a Calcium Channel", J. Biol. Chem., 1996; 271: 5879-5776).

TABLE 1 Compound Structure IC50 (μM) on Link Site a2d (±) -2-Aza- 0.35 spiro [4.5] decane-4-carboxylic acid hydrochloride (R) -2- Aza-spiro [4.5] decane-4- 0.16 carboxylic acid hydrochloride (S) -2-Aza spiro [4.5] decane-4-carboxylic acid hydrochloride (±) -2-Aza-spiro [3.5] nonane-1-carboxylic acid hydrochloride (+) - [3aS- (3a, 7aa)] - (Octahydro-> 10 isoindol-3a-yl) -acetic acid trifluoroacetate TABLE 1 (cont.) Compound Structure IC50 (μM) on Link Site a2d Table 1 above shows the binding affinity of the compounds of the invention to the a2d subunit. The compounds of the invention are compared to Neurontin®, a commercial drug effective in the treatment of such diseases as epilepsy. Neurontin® is the 1- (aminomethyl) -cyclohexaneacetic acid of the structural formula Gabapentin (Neurontin®) is approximately 0.10 to 0.12 μM in this test. It is expected that the compounds of the present invention, therefore, exhibit pharmacological properties comparable to gabapentin. For example, as agents for seizures, anxiety and pain. The present invention also relates to the therapeutic use of the mimetic compounds as agents for neurodegenerative diseases.

Such neurodegenerative diseases are, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis. The present invention also covers the treatment of neurodegenerative diseases called acute brain injuries. These include but are not limited to: stroke, brain trauma and asphyxia. Stroke refers to a cerebrovascular disease and can also be referred to as a cerebrovascular incident (CVA) and includes acute thromboembolic stroke. Stroke includes global and focal ischemia. Also included are temporary cerebral ischemic attacks and other cerebral vascular problems accompanied by cerebral ischemia. A patient undergoing carotid endoarterectomy specifically or other vascular or cerebrovascular surgical procedure in general or diagnostic vascular procedures including cerebral angiography and the like.

Other incidents include trauma to the head, trauma to the spine or damage due to anoxia, hypoxia, hypoglycemia, hypotension as well as similar damage observed during the events of embolism, hyperfusion and hypoxia. The present invention is useful for the treatment of several incidents, for example, during cardiac bypass surgery in incidents of intracranial hemorrhages, perinatal asphyxia, in cardiac arrest and epileptic status. Pain refers from acute to chronic pain. Acute pain is usually of short duration and is associated with hyperactivity of the sympathetic nervous system. Examples are postoperative pain and allodynia. Chronic pain is usually defined as pain that persists for 3 to 6 months and includes somatogenic pain and psychogenic pain. Another pain is the nociceptive. Another kind of pain is caused by damage or infection of the peripheral sensory nerves. It includes, but is not limited to, peripheral nerve trauma pain, herpes virus infection, diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain is also caused by damage to the nerve of chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiencies. Neuropathic pain includes, but is not limited to pain caused by nerve damage such as, for example, the pain that is suffered by diabetes. Psychogenic pain is one that occurs without any organic origin such as pain in the lower back, atypical facial pain and chronic headache. Other types of pain are: inflammatory pain, osteoarthritic pain, trigeminal neuralgia, cancer pain, diabetic neuropathy, joint pain syndrome, acute herpes and postherpetic neuralgia, causalgia, branchial plexus avulsion, occipital neuralgia, gout, amputation, burn and other forms of neuralgia, idiopathic and neuropathic pain syndrome. An empowered physician will be able to determine the administration of the methods of the present invention in the appropriate situation in which the subjects are susceptible to or at risk of, for example, stroke, as well as those suffering from the apoplexy. The compounds of the invention are also expected to be useful in the treatment of depression. Depression can be the result of an organic disease, secondary to stress associated with personal or idiopathic loss by nature. There is a strong tendency for the familiar occurrence of some forms of depression that suggest a mechanical cause in at least some forms of depression. The diagnosis of depression is first made by quantifying the alterations of the patients' moods. These mood assessments are usually performed by a physician or quantified by a neuropsychologist using valid classification scales, such as the Hamilton Depression Rating Scale or the Brief Psychiatric Rating Scale. Other scales have been developed to quantify and measure the degree of mood alterations in patients with depression, such as insomnia, difficulty concentrating, lack of energy, feelings of low self-esteem and guilt. The standards for the diagnosis of depression as well as all psychiatric diagnoses are gathered in the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) referred to as the DSM-IV-R manual published by the American Psychiatric Association, 1994. GABA is a neurotransmitter inhibitor of the central nervous system. Within the general context of inhibition, it appears that GABA-mimetics can decrease or inhibit brain function and therefore slow down function and decrease the mood that leads to depression. The compounds of the present invention can produce an anticonvulsant effect by increasing the GABA created again in the synaptic junction. If gabapentin truly increases GABA levels or the effectiveness of GABA in the synaptic junction, then it can be classified as a GABA-mimetic and can decrease or inhibit brain function and can therefore slow down the function and decrease the mood that leads to the Depression. The fact that a GABA agonist or a mimetic GABA can work just in the opposite way by increasing mood and thus being an antidepressant, is a new concept, different from the prevailing opinion so far of GABA activity. It is also expected that the compounds of the present invention are useful in the treatment of anxiety and panic as demonstrated by standard pharmacological procedures.

MATERIAL AND METHODS Induced Hyperalgesia-Carrageenan The beginnings of nociceptive pressure were measured in the pressure test of the leg of the rat using an analgesimeter (Randall-Sellito method: Randall LO, Sellito JJ, "A method for mesurement of analgesic activity on inflamed tissue". Arch. Int. Pharmacodyn., 1957; 4: 409-419). Male Sprague-Dawley rats (70-90 g) were trained in this apparatus before the day of the test. The pressure was applied gradually to the hind paw of each rat and the nociceptive starts were determined as the pressure (g) required to achieve leg withdrawal. A closing point of 250 g was used to prevent any damage to the leg tissue. On the day of the test, two to three normal measurements were taken before the animals were given 100 μl of 2% carrageenan by intraplantar injection into the right hind paw. Again the nociceptive beginnings were taken for 3 hours after carrageenan to establish which animals exhibited hyperalgesia. The animals were dosed with gabapentin (3-300 mg, sc), morphine (3 mg / kg, sc) or saline in 3.5 hours after carrageenan and the nociceptive onset was examined at 4, 4.5 and 5 hours post -carrageenan. (R) -2-Aza-spiro [4.5] decane-4-carboxylic acid hydrochloride was tested in the previous model of hyperalgesia induced carrageenan. The compound was dosed orally at 30 mg / kg and 1 hour post-dose provided a maximum possible effect percentage (MPE) of 53%. At two hours post-dose, he provided only 4.6% MPE.

Induced Tonic Accesses - Semicarbazide Tonic accesses were induced in mice by subcutaneous administration of semicarbazide (750 mg / kg). The latent state was recorded to the tonic extension of the front legs. Any of the mice that did not convulse within 2 hours after semicarbazide were considered protected and provided a maximum latent marking of 120 minutes.

Animals Male Hooded Lister rats (200-250 g) from Interfauna (Huntingdon, GB) were obtained and male TO mice (20-25 g) were obtained from Bantin and King an (Hull, GB). Both species of rodents were housed in groups of six. Ten Common Tities (Callithrix Jacchus) were housed in pairs weighing between 280 and 360 g, bred in the School of Medicine of the University of Manchester (Manchester, GB). All the animals were housed in a cycle of 12 light / dark hours (lights on for 7.00 hours) and with food and water ad libitum.

Drug Administration The drugs were administered either intraperitoneally (IP) or subcutaneously (SC) 40 minutes before the test in a volume of 1 ml / kg for rats and marmosets and 10 ml / kg for mice.

Light / Dark Box for Mice The device is an open box at the top, 45 cm long, 27 cm wide and 27 cm high, divided into a small area (2/5) and a large area (3 / 5) by a division extending 20 cm above the walls (Costall B., et al., "Exploration of mice in a black and white box: validation as a model of anxiety." Pharmacol. Biochem.

Behav., 1989; 32: 777-785). There is an opening of 7.5 x 7.5 cm in the center of the division at ground level. The small compartment is painted black and the large compartment is white. The white compartment was illuminated with a 60-W tungsten bulb. The lab lit up with a red light. Each mouse was studied by placing it in the center of the white area and allowing it to explore the new environment for 5 minutes. The time consumed on the illuminated side was measured. (Kilfoil T., et al., "Effects of anxiolytic and anxiogenic drugs on exploratory activity in a simple model of anxiety in mice." Neuropharmacol., 1989; 28: 901-905).

Raised X Maze for Rats A standardized elevated X-labyrinth was automated (Handley SL, et al., "Effects of alpha-adrenoceptor agonist and antagonists in a maze-exploration model of 'fear' -motivated behavior." Naunyn-Schiederberg's Arch. Pharmacol ., 1984; 327: 1-5) as previously described (Field, et al., "Automation of the rat elevated X-maze test of anxiety", Br. J. Pharmacol., 1991; 102 (Suppl): 304P). The animals were placed in the center of labyrinth X in front of one of the open areas. To determine the anxiolytic effects, the time at the entrances and exits of the intermediate sections of the open areas during the 5-minute test period was measured. (Costall, et al., "Use of the elevated plus maze to asses anxiolytic potential in the rat." Br. J. Pharmacol., 1989; 96 (Suppl): 312P).

Human Threat Test for Titi The total number of bodily postures shown by the animal towards the threat stimulus (a human staying approximately 0.5 m away from the marmoset cage and staring at the eyes) was recorded during a trial period two minutes Registered body postures are hair ruffling intervals, tail postures, cage marking / hooks by smell, erect positions, withdrawals, and bowing of the back. Each animal was exposed to the threat stimulus twice on the test day before and after treatment with the drug. The difference between the two marks was analyzed by the variance analysis followed by Dunnett's test. All treatments were performed in the SC in at least 2 hours after the first threat (control). The pretreatment time for each compound is 0 minutes.

Rat Conflict Test The rats were trained to press levers for food rewards in operating chambers. The program consists of alterations of four periods of 4 minutes without punishment in variable intervals of 30 seconds indicated by the lights on of the camera and three periods of 3 minutes of punishment in a fixed radius 5 (by concomitant shock in the legs upon delivery). of food) indicated by the lights off of the camera. The degree of shock on the legs was adjusted for each rat to obtain approximately 80 to 90% suppression of the response compared to the response without punishment. The rats received saline vehicles on training days.

Anticonvulsant Efficiency of the Model for DBA2 Mice All procedures were carried out in accordance with the NIH Guide for the Care and Use of Laboratory Animals under a protocol approved by the Parke-Davis Committee for the Use of Animals. Male DBA / 2 mice from 3 to 4 weeks were taken from Jackson Laboratories, Bar Harbor, Maine. Immediately before the anticonvulsant test, the mice were placed inside a wire mesh, a 10.16 cm2 square, suspended from a steel bar. The frame was slowly inverted by 180 ° and the mice were observed for 30 seconds. Any mouse that fell from the wire mesh was marked as ataxic (Coughenour LL, McLean JR, Parker RB, "A new device for the rapid measurement of impaired motor function in mice" Pharm. Biochem. Behav., 1977; 6 (3 ): 351-3). The mice were placed inside an enclosed plastic acrylic chamber (21 cm in height, approximately 30 cm in diameter) with a high frequency microphone (4 cm in diameter) in the center of the top cover. An audio signal generator (Protek model B-810) was used to produce a continuous sinusoidal tone that was linearly swept at a frequency between 8 kHz and 16 kHz once every 10 msec. The average sound pressure level (SPL) during the stimulation was approximately 100 dB on the floor of the chamber. The mice were placed inside the chamber and allowed to acclimate for 1 minute. The DBA / 2 mice in the sample group responded to the sound stimulus (applied until the tonic extension occurred, or for a maximum of 60 seconds) with a characteristic access sequence consisting of a wild stroke followed by clonal accesses and later by tonic extension and finally by respiratory arrest and death in more than 80% of the mice. In the mice shown, the total sequence of respiratory arrest accessions lasted approximately 15 to 20 seconds. The incidence of all access phases in the mice sample treated with drugs was recorded and the occurrence of tonic accesses was used to calculate ED50 anticonvulsant values by probity analysis (Litchfield JT, Wilcoxon F. "A simplified method for evaluating dose-effect experiments, "J. Pharmacol., 1949; 96: 99-113). The mice were used only once per test at each dose point. The groups of DBA / 2 mice (n = 5-10 per dose) were tested for the measurement of sound induced access responses in 2 hours (previously determined maximum effect time) after the drug was given orally. All the drugs of the present study were dissolved in distilled water and provided by forced oral feeding in a volume of 10 ml / kg of body weight. Compounds that were insoluble were suspended in 1% carboxymethocellulose. The doses are expressed as half the weight of the active drug.

The compounds of the present invention are also expected to be useful in the treatment of pain and phobic diseases (Am. J. Pain Manag., 995; 5: 7-9). It is also expected that the compounds of the present invention will be useful in the treatment of symptoms of acute or chronic manias, simple disorders, or recurrent depression. They are also expected to be useful in the treatment and / or prevention of bipolar diseases (U.S. Patent Number 5,510,381). The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention may be administered by injection, which may be intravenous, intramuscular, intracutaneous, subcutaneous, intraduodenal or intraperitoneal. Also, the compounds of the present invention can be administered by inhalation, for example intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be apparent to those skilled in the art that the following dosage forms may comprise as the active component either a compound of Formula 1 or a pharmaceutically acceptable salt of the corresponding compound of Formula I. For the preparation of the pharmaceutical compositions of the compounds of the present invention, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, caches, suppositories and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In the powders, the carrier is a finely divided solid that is mixed with the finely divided active component.

In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and is compacted in the desired shape and size. The powders and tablets preferably contain from five to ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low-grade wax. melting point, cocoa butter, and the like. The term "preparation" includes the formulation of the active compound with the encapsulating material as a carrier that provides a capsule in which the active compound with or without other carriers is surrounded by a carrier, which is thus in association with the carrier. Similarly, cachets and pills are included. It includes tablets, powders, capsules, pills, cachets and pills. Tablets, powders, capsules, pills, cachets and pills can be used as solid dosage forms suitable for oral administration. For the preparation of suppositories, a low-melting wax is first melted, such as a mixture of fatty acids and glycerides or cocoa butter and the active compound is dispersed homogeneously therein by stirring.

Subsequently, the homogeneous mixture dissolved in molds of suitable size is added, to cool down and thereby solidify. Liquid form preparations include solutions, suspensions and emulsions, for example water or propylene glycol water solutions. Liquid preparations for parenteral injection can be formulated in aqueous solutions of polyethylene glycol.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickeners as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with a viscous material, such as synthetic or natural gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. Also included are solid form preparations which are intended to be converted prior to their use to liquid form preparations for oral administration. Said liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active compound, colorants, flavors, stabilizers, buffers, natural and artificial sweeteners, dispersants, thickeners, solubilizing agents and the like. It is preferred that the pharmaceutical preparation be in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dose form can be a packaged preparation, the package contains discrete quantities of the preparation, such as packed tablets, capsules and powders in small vials or ampoules. Also, the unit dosage form can be a capsule, a tablet, cachet or a tablet by itself, or it can be the appropriate number of any of these in packaged form. The amount of active component in a unit dose preparation can be varied or adjusted from 0.1 mg to 1 g in accordance with the particular application and potency of the active component. In medical use the drug can be administered three times a day, as for example, capsules of 100 or 300 mg. The composition may, if desired, also contain other compatible therapeutic agents.

In therapeutic use, the compounds used in the pharmaceutical method of this invention were administered in an initial dose of about 0.01 mg to about 100 mg / kg daily. A range of about 0.01 mg to about 100 mg / kg was preferred. The doses, however, can vary depending on the requirements of the patient, the severity of the condition to be treated and the component used. The determination of the appropriate dose for a particular situation is within the reach of the person skilled in the art. Generally, treatment starts with smaller doses that are less than the optimal dose of the compound. After this, the dose is increased in small increments until the optimal effect is reached under the circumstances. For convenience, the total daily dose can be divided and administered in portions during the day, if desired. The following examples are illustrative of the present invention, are not to limit the scope thereof. EXAMPLE 1 ) (2. 3) (5) (4) Reagents: (i) T iCl, MeO 2 CCH 2 CO 2 Me, pyridine, tetrahydrofuran; (ii) N-Benzylglycine Hydrochloride, Et 3 N, paraformaldehyde, PhH; (ip) Pearlman catalyst, methanol, H2; (iv) 6N HCl.

Dimethyl ester of 2-cyclohexylidene malonic acid (2) To 20 ml of tetrahydrofuran cooled to -78 ° C was added slowly, under an argon atmosphere, TiCl 4 (1 M in CH 2 CH 2, 100 ml, 100 mmol). After the addition was complete, the reaction mixture was heated above -10 ° C. After the mixture, dimethylmalonate (6.73 g, 51 mmol), cyclohexanone 1 (5 g, 51 mmol) for 5 minutes and pyridine (16.4 ml, 201 mmol) were added successively for 1 hour 30 minutes. The brown suspension was subsequently warmed to room temperature, stirred overnight and diluted with water (50 ml). The phases were separated and the organic phase was washed with water, dried over MgSO4 and the solvent removed in vacuo. The crude oil was chromatographed on silica gel (ether / heptane 1: 1) to give 2 as a light yellow solid (6.35 g, 30 mmol, 58%). 1 H NMR (CDCl 3) d ppm: 1.6 (m, 6H); 2.5 (m, 4H); 3.75 (s, 6H). MS ES + [MW + 1] +: 213. 2-Benzyl-2-aza-spiro [4.5] decane-4,4-dicarboxylic acid dimethyl hydrochloride (3) A solution of dimethyl (cyclohexylidene) malonate 2 (594 mg, 2.8 mmol), N-benzylglycine hydrochloride (1.41 g, 6.99 mmol), triethylamine (0.97 ml, 6.95 mmol) and paraformaldehyde (671 mg, 22.36 mmol) in benzene (18 ml) was slowly heated above 125 ° C (oil bath) (Dean-Stark). After stirring for 2 hours, the reaction mixture was cooled to room temperature, diluted with toluene (20 ml) and washed with brine. The aqueous phase was extracted with toluene (2 x 20 ml). The organic phases were combined, dried over MgSO4 and evaporated to give a brown oil which was purified by silica gel chromatography (EtOAc / heptane 1: 3). The resulting light yellow oil was diluted in diethyl ether (10 ml) and the compound was extracted with 2N HCl (2 x 5 ml). The aqueous phases were combined, washed with diethyl ether and concentrated in vacuo to give 3 as a white solid (238 mg, 0.62 mmol, 22%). 1 H NMR (D 2 O) d ppm: 1.2 to 1.9 (m, 10H); 3.65 and 3.9 ([ABjq, 2H); 3.9 (d, 6H); 4.1 and 4.25 ([AB] q, 2H); 4.65 (s, 2H); 7.6 (m, 5H). MS ES + [MW + 1] +: 346. 2-Aza-Spiro [4.5] decane-4,4-dicarboxylic acid dimethyl ester hydrochloride (4) A solution of 3 (238 mg, 0.62 mmol) and Palladium hydroxide in charcoal (47 mg, 20% w / w) ) in methanol (10 ml) was stirred overnight at 40 ° C under a hydrogen atmosphere (55 psi). The catalyst was filtered through a pad of celite and the filtrate was evaporated in vacuo to give 4 as a yellow solid (170 mg, 0.58 mmol, 93%). 1 H NMR (D 2 O) d ppm: 1.2 to 1.8 (m, 10H); 3.65 (s, 2H); 3.9 (s, 6H); 4.01 (s, 2H). MS ES + [MW + 1] +: 256. 2-Aza-espyro [4.5] decane-4-carboxylic acid hydrochloride (5) A solution of 4 (170 mg, 0.58 mmol) in 6N HCl (5 ml) was stirred overnight at 145 ° O After cooling, The solvent was removed under vacuum to yield 5 as a light yellow solid (153 mg, 0.58 mmol, quant). 1 H NMR (D 2 O) d ppm: 1.39 to 1.8 (m, 10H); 3.1 (t, 1H); 3.4 ([ABjq, 2H); 3.7 (d [AB] q, 2H). MS ES + [MW + 1] +: 184.

C, H, N, Cale, for C 10 H 17 NO 2 »1.75 HC. O H 2 O: C, 45.31; H, 7.89; N, 5.28. Observed: C, 45.65; H, 7.69; N, 5.62.

EXAMPLE 1A Bn = PhCH2-, Z = PhCH2OCO- Reagents: (i) HCl «BnNHCH2CO2H, Et3N, HCHO, PhH, reflux (82%); (I) 6N HCl reflux (94%); (iii) MeOH, HCl, reflux (65%); (iv) Pd (OH) 2 / C, H2j MeOH (97%); (v) BnOCOCI, Py, CH2Cl2, (88%); (vi) Dioxane / AcOH Na (89%); (vii) CH2Cl2, (CoCl) 2, HCONMe2 subsequently (R) - (+) - 1- (2-Naphthyl) ethylamine followed by flash chromatography (20a) - 43% and (20b) -39%; (viii) 6N HCl, reflux THF (73%); (ix) 6N HCl, reflux THF (78%). 2-Benzyl-2-aza-spiro [4.5] decane-4-carboxylic acid methyl ester (4) A solution of (1) (4g, 20.70 mmol), N-benzylglycine hydrochloride (10.4 g, 51.57 mmol), triethylamine (7.2 ml, 51.65 mmol) and paraformaldehyde (5.2 g, 173.30 mmol) in benzene (120 ml) was refluxed for 2 hours using a Dean-Stark apparatus. After cooling, the reaction mixture was diluted with toluene (200 ml) and washed with brine. The aqueous phase was extracted with toluene (3x30 ml). The organic extracts were combined, dried over MgSO 4 and concentrated in vacuo. The crude oil was purified by silica gel chromatography in EtOAc / heptane (1: 3) to give a yellow oil which was diluted in ether (30 ml) and extracted with 3N HCl (3x25 ml). The aqueous phase was washed with ether (2x30 ml) and concentrated in vacuo to give (2) as a white powder (6.20 g, 17.08 mmol) which was used without any further purification. A solution of (2) (6.2 g, 17.08 mmol) in 6N HCl (120 ml) was refluxed overnight. Evaporation of the solvent in vacuo gave 5g (16.13 mmol; 77% of (1)) of (3) as a pale yellow solid which was immediately esterified. Acetyl chloride (5 ml, 70.32 mmol) was added slowly to methanol (100 ml) at 0 ° C, under an argon atmosphere. After stirring for 10 minutes, this solution was transferred to a flask containing (3) (5 g, 16.13 mmol), under an argon atmosphere. The reaction mixture was subsequently stirred at 95 ° C for 3 hours. After cooling, the methanol was removed in vacuo. The residue was basified with saturated aqueous Na2CO3 and extracted with ether (3x30 ml). The organic phases were combined, dried over MgSO 4 and concentrated to give 3 g (10.44 mmol, 50% of (1)) of (4) as a pale yellow liquid. 1 H NMR (CDCl 3) 400 MHz d: 1.0 to 1.7 (m, 10H); 2.25 (d, 1 H); 2.65 to 2.9 (m, 4H); 3.6 ([AB] q, 2H); 3.65 (s, 3H, OCH3)); 7.3 (m, 5H, Ph). MS (ES +) m / e: 288 ([MH] +, 100%). 2-Aza-spiro [4.5] decane-2,4-dicarboxylic acid 2-benzyl ester-4-methyl ester (6) A solution of (4) (3g, 10.44 mmol) and 10% Pd (OH) 2 / C (0.60 g, 20% w / w) in methanol (50 ml) was stirred for 24 hours at 40 ° C under an atmosphere of dry hydrogen gas. The catalyst was filtered through a pad of celite and the filtrate was concentrated in vacuo to give 2g (0.14 mmol, 97%) of (5) as a colorless oil which was used without any further purification. To a solution of (5) (2g, 10.14 mmol) in dry dichloromethane (100 ml) was added successively at 0 ° C under an atmosphere of argon, pyridine (2.04 ml, 25.35 mmol) and benzylchloroformate (2.89 ml, 20.24 mmol). . Subsequently, the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was washed (2x50 ml) with 1 N HCl, dried over MgSO and concentrated in vacuo. The crude oil was purified by flash chromatography of silica gel in ether / heptane (1: 1) to give 2.97 g (8.96 mmol, 88%) of (6) as a colorless oil. 1 H NMR (CDCl 3) 400 MHz d: 1.15 to 1.7 (m, 10H); 2.8 (m, 1 H); 3.3 (m, 1 H); 3.45 to 3.8 (m, 6H); 5.15 ([ABjq, 2H, PhCJi >); 7.3 (m, 5H, Ph). MS (ES +) m / e: 332 ([MH] +, 100%). 2-Aza-spiro [4.5] decane-2,4-dicarboxylic acid 2-benzyl ester (7) To a solution of (6) (300 mg, 0.9 mmol) in a dioxane / water mixture (6 ml) , 9: 4) was added a 2 M NaOH solution (0.90, 1.8 mmol). The reaction mixture was stirred at 35 ° C for 6 hours. The solvents were removed in vacuo. The residue was diluted in water (15 ml) and washed with diethyl ether (3x10 ml). The aqueous phase was acidified with 2N HCl and extracted with ethyl acetate (3x15 ml). The ethyl acetate extracts were combined, dried over MgSO and concentrated to give 254 mg (0.8 mmol, 89%) of (7) as a colorless gum. 1 H NMR (CDCl 3) 400 MHz d: 1.2 to 1.75 (m, 10H); 2.8 (m, 1H); 3.3 (m, 1 H); 3.5 to 3.8 (m, 3H); 5.1 (ABq, 2H); 7.3 (m, 5H). MS (ES +) m / e: 318 ([MH] +, 100%).

Benzyl ester of (4S, 1'R) -4- (1'-Naphthalene-2-yl-ethylcarbamoyl) -2-aza-spiro [4.5] decane-2-carboxylic acid (8a) and Benzyl ester of acid (4RJ1 'R) -4- (1'-Naphthalene-2-yl-ethylcarbamoyl) -2-aza [4.5] decane-2-carboxylic acid (8b) To a cooled (0 ° C) solution of (7) (1.71 g; 5.38 mmol) in dry dichloromethane (35 ml) was added successively under an atmosphere of argon, oxalyl chloride (0.56 ml, 6.42 mmol) and dimethylformamide (20 μl, 0.26 mmol). The reaction mixture was stirred at 0 ° C for 30 minutes and then stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was diluted in dry dichloromethane (35 ml). This solution was subsequently added to a solution of (R) - (+) - 1- (2-naphthyl) ethylamine (1.10 g, 6.42 mmol) and triethylamine (0.90 ml, 6.42 mmol) in dry dichloromethane (50 ml) under a argon atmosphere. The reaction mixture was stirred at room temperature overnight. 2N HCl (30 ml) was added and the aqueous and organic phases were separated. The organic phase was washed with water (30 ml), dried over MgSO 4 and concentrated to give a pale yellow oil which was purified by silica gel chromatography in EtOAc / heptane (1: 1) to give 1.1 g (2.34 mmol; 43%) of (8a) and 1.0 g (2.12 mmol, 39%) of (8b) as white solids. 1 H NMR (CDCIa) 400 MHz d: (8a): 1.2 to 1.65 (m, 13H); 2.4 (m, 1H); 3.35 (d, 1 H); 3.5 to 3.8 (m, 3H); 5.1 (m, 2H); 5.3 (m, 1 H); 5.7 (t, 1 H); 7.3 to 7.8 (m, 12H). (8b): 1.2 to 1.65 (m, 13H); 2.4 (m, 1 H); 3.25 (d, 1 H); 3.5 to 3.8 (m, 3H); 5.1 (m, 2H); 5.3 (m, 1H); 5.7 (t, 1 H); 7.3 to 7.8 (m, 12H). MS (ES +) m / e: (8a): 471 ([MH] +, 100%); (8b): 471 ([MH] +, 100%).

(S) -2-Aza-spiro [4.5] decane-4-carboxylic acid (9a) To a solution of (8a) (770 mg, 1.64 mmol) in THF (5 mL) was added aqueous 6N HCl (40 mL). ml). The reaction mixture was stirred under reflux overnight. After cooling, the reaction mixture was washed with EtOAc (2x20 ml). The phases were separated and the aqueous phase was concentrated to dryness in vacuo. The crude residue was dissolved in 6N aqueous HCl (40 ml) and the reaction mixture was stirred under reflux for 60 hours. After cooling, the reaction mixture was washed with EtOAc (2x20 ml). The phases were separated and the aqueous phase was concentrated to dryness to leave a solid which was dissolved in water. Removal of the water under vacuum led to (9a) as a white powder (263 mg, 1.20 mmol, 73%). 1 H NMR (CDCl 3) 400 MHz d: 1.2 to 1.8 (m, 10H); 3.1 (t, 1 H); 3.4 ([AB] q, 2H); 3.7 (m, 2H). MS (ES +) m / e: 184 ([MH] +, 100%).

Acid (R) "2-Aza-spiro [4.5] decane-4-carboxylic acid (9b) (8b) (553 mg, 1.17 mmol) was converted to 200 mg (0.91 mmol, 78%) of (12b) by itself procedure for (9a) to (12a). 1 H NMR (CDCl 3) 400 MHz d: 1.2 to 1.8 (m, 10H); 3.1 (t, 1 H); 3.4 ([ABjq, 2H); 3.7 (m, 2H). MS (ES +) m / e: 184 ([MH] +, 100%).

EXAMPLE 2 l < iv > < * > m Reagents: (i) BnOCH2CHO, LiN (iPr) 2, THF, -78 ° C to -20 ° C; (ii) AICI3, LiAIH4, Et2O; (iii) BOC2O, dichloromethane; (iv) MeSO2CI, Et3N, dichloromethane; (v) NaH, dimethylformamide; (vi) Ammonium format, 10% Pd / C, MeOH; (vii) NalO4, RuCI3, CCI4, CH3CH, H2O; (viii) 1 N HCl (g) in ethyl acetate. 1- (2-Benzyloxy-1-hydroxy-ethyl) -cyclohexanecarbonitrile (2) Lithium diisopropylamide was prepared by dropwise addition of n-BuLi (2.03 ml, 2.5 M in Hexanes, 5.08 mmol) to a stirred and cooled solution ( -10 ° C) of -P -Pr2NH (0.84 mL, 6.0 mmol) in dry tetrahydrofuran (40 mL). Stirring was continued for 20 minutes. The mixture was cooled to -78 ° C and cyclohexane carbonitrile 1 (500 mg, 4.62 mmol) was added over 5 minutes. After an additional 30 minutes, benzyloxyacetaldehyde (0.97 ml, 6.93 mmol) was added dropwise. Stirring was continued at -78 ° C for 7 hours. Subsequently the reaction mixture was stirred overnight at -20 ° O saturated aqueous NH 4 Cl (10 ml) was added and the mixture was extracted with diethyl ether (2x 20 ml), dried over MgSO 4 and evaporated. The residue was purified by silica gel chromatography (ether / heptane 1: 1) to give 2 as a white solid (872 mg, 3.37 mmol, 73%). 1 H NMR (CDCl 3) d ppm: 1.1 to 1.8 (m, 9H); 2.2 (d, 1 H); 2.75 (s, 1 H); 3.6 to 3.8 (m, 3H); 4.6 ([ABjq, 2H); 7.4 (m, 5H). MS ES + [MW + 1] +: 259. 1 - . 1- (1-Aminomethyl-cyclohexyl) -2-benzyloxy-ethanol (3) A ACI3 (410 mg, 3.07 mmol) was added at -78 ° C and under an argon atmosphere, 3 ml of diethyl ether. The dry ice bath was removed. The mixture was stirred at room temperature for 10 minutes and then added to LiA1H4 (3.02 ml, 1 M in diethyl ether, 3.02 mmol). A solution of 2 (300 mg, 1.16 mmol) in diethyl ether (3 ml) was subsequently added over the course of 2 minutes and the reaction mixture was stirred overnight at room temperature. The mixture was warmed by the cautious addition of water (2 ml) followed by the addition of 10% H2SO4 (30 ml). The aqueous phase was washed with diethyl ether (3 x 15 ml), basified with NaOH granules (excess) and extracted with diethyl ether (3 x 15 ml). The organic phases were combined, washed with brine and dried over MgSO and evaporated to give 3 as a colorless oil (230 mg; 0. 87 mmol; 76%) that was used without further purification. 1 H NMR (CDCl 3) d ppm: 1.2 to 1.7 (m, 10H); 2.75 (d, 1H); 2.95 (s, 1H); 3.6 (dd, 1 H); 3.7 (dd, 1 H); 4.6 ([AB] q, 2H); 7.3 (m, 5H). MS ES + [MW + 1j +: 264. [1- (2-Benzyloxy-1-hydroxy-ethyl) -cyclohexylmethyl] -carbamic acid tert-butyl ester (4) A solution of 3 (244 mg, 0.92 mmol) and BOC2O (242 mg, 1.11 mmol) in CH2Cl2 (8 ml) was stirred at room temperature for 24 hours under an argon atmosphere. The solvent was removed in vacuo and the crude oil was purified by silica gel chromatography (ether / heptane 1: 1) to give 4 as a colorless oil (298 mg, 0.82 mmol, 89%). 1 H NMR (CDCl 3) d ppm: 1.1 to 1.6 (m, 10H); 1.4 (s, 9H); 2.8 (s, 1 H); 3.1 (dd, 1 H); 3.35 (dd, 1 HOUR); 3.5 (t, 1 H); 3.65 (dd, 1 H), 3.75 (dd, 1 H); 4.6 ([ABjq, 2H); 5.5 (bs, 1H); 7.3 (m, 5H).

MS ES + [MW + 1] +: 364.

Methanesulfonic acid 2-benzyloxy-1- [1- (tert-butoxycarbonylamino-methyl) -cydohexyl] -ethyl ester (5) To a cooled (-10 ° C) solution of 4 (290 mg, 0.79 mmol) and triethylamine (0.33) ml; 2. 39 mmol) in CH 2 Cl 2 (5 ml) was added, under an argon atmosphere, MsCl (0.154 ml, 1.93 mmol) diluted in CH 2 Cl 2 (0.5 ml). Subsequently, the reaction mixture was stirred at room temperature for 2 days. The solvent was removed in vacuo and the residue was diluted in diethyl ether, washed with water, dried over MgSO 4 and concentrated. The crude oil was purified by silica gel chromatography (ether / heptane 1: 1) to give 5 as a colorless oil (200 mg, 0.45 mmol, 57%). 1 H NMR (CDCl 3) d ppm: 1.2 to 1.6 (m, 10H); 1.2 (s, 9H); 3 (s, 1 H); 3.05 (dd, 1 H); 3.25 (dd, 1 HOUR); 3.8 (m, 2H); 4.55 ([ABjq, 2H); 4.75 (m, 1 H); 5.05 (m, 1 H); 7.3 (m, 5H).

MS ES + [MW + 1] +: 442.

Ester tert-butyl 1-benzyloxymethyl-2-aza-spiro [3.5] nonane-2-carboxylic acid (6) A solution of 5 (2.53 g, 5.73 mmol) and NaH (460 mg, 60% w / w in oil; 11.47 mmol) in dry DMF (115 ml) was stirred at 45 ° C for 1 hour under an argon atmosphere. The reaction was warmed by cautious addition of saturated NH 4 Cl (200 mL) and the aqueous phase was extracted with diethyl ether (2 x 100 mL). The organic phases were combined, dried over MgSO 4 and evaporated. The residue was purified by silica gel chromatography (ether / heptane 1: 2) to give 6 as a colorless oil (1.20 g, 3.48 mmol, 59%). 1 H NMR (CDCl 3) d ppm: 1.2 to 1.8 (m, 10H); 1.4 (s, 9H); 3.45 ([ABjq, 2H); 3.7 (m, 2H); 3.85 (m, 1H); 4.55 ([ABjq, 2H); 7.3 (m, 5H). MS ES + [MW + 1] +: 346. 1-hydroxymethyl-2-aza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester (7) A solution of 6 (349 mg, 1.01 mmol), ammonium formate (638 mg, 10.1 mmol) and % Pd / C (349 mg, 1 eq. P / p) in methanol (20 ml) was heated to reflux for 2 hours. Ammonium formate (638 mg, 10.1 mmol) and 10% Pd / C (175 mg, 0.5 eq p / p) were added and the reaction mixture refluxed for an additional 2 hours. After cooling, the catalyst was filtered through a pad of celite and the filtrate was evaporated. The crude oil was purified by silica gel chromatography (ether / heptane 4: 1) to give 7 as a white solid (193 mg, 0.76 mmol, 75%). 1 H NMR (CDCl 3) d ppm: 1.1 to 1.8 (m, 10H); 1.45 (s, 9H); 3.55 ([ABjq, 2H); 3.7 (m, 1H); 3.9 (m, 2H); 4.45 (bs, 1H). MS ES + [MW + 1j +: 256. C, H, N Cale: C, 65.85; H, 9.87; N, 5.48.

Observed: C, 65.54; H, 9.65 N, 5.39. 2-Aza-spiro [3.5] nonane-1,2-dicarboxylic acid (2) -butyl ester (8) A 7 (212 mg, 0.83 mmol) dissolved in a mixture of CCI (1.7 ml), CH3CN (1.7 ml) ) and water (2.5 ml) was added NalO (710 mg, 3.32 mmol). After 15 minutes, hydrated RuCI3 (4.8 mg, 2.2 mol%) was added and the reaction mixture was stirred at room temperature for 2 hours. The mixture was subsequently extracted with CH2Cl2 (3x5 ml), washed with water, dried over MgSO4 and concentrated. The crude oil was diluted with diethyl ether (5 ml) and saturated aqueous Na 2 CO 3 (5 ml) was added. The aqueous phase was washed with diethyl ether (3 x 5 ml), acidified to pH = 3 with 1N HCl and extracted with diethyl ether (3 x 5 ml). The organic phases were combined, washed with water and concentrated in vacuo to give 8 as a white solid (185 mg, 0.69 mmol, 83%). 1 H NMR (CDCl 3) d ppm: 1.2 to 1.8 (m, 10H); 1.5 (s, 9H); 3.6 ([ABjq, 2H); 4.3 (s, 1 H). MS ES + [MW + 1j +: 270. C, H, N Calc: C, 62.43; H, 8.60; N, 5.20. Observed: C, 62.40; H, 8.75; N, 5.01. 2-Aza-spiro [3.5] nonane-1-carboxylic acid hydrochloride (9) Compound 8 (21.5 mg, 0.079 mmol) was dissolved in a solution of 1M HCl (g) in ethyl acetate (0.4 ml, 0.4 mmol) under an atmosphere of argon. The reaction mixture was stirred at room temperature for 5 hours. The white precipitate was collected by filtration and washed several times with dry diethyl ether (2 ml) and dried under vacuum to give 9 as a white powder (15.2 mg, 0.074 mmol, 92%). 1 H NMR (CDCl 3) d ppm: 1.03 to 1.84 (m, 10H); 3.7 ([ABjq, 2H); 4.4 (s, 1 H). MS ES + [MW + 1j +: 170.

MP: 163-165 ° C. C.H.N Cale. C 9 H 15 NO 2"1.0 HCl: C, 52.55; H, 7.84; N, 6.81. Observed: C, 52.50; H, 7.74; N, 6.88.

EXAMPLE 3 Reagents: (i) MeNO2, (Bu) 4N + F_; tetrahydrofuran; (ii) Sponge Ni, H2, MeOH; (iii) (BOC) 2 O, 4-dimethylamino pyridine, Et 3 N, tetrahydrofuran; (iv) LiN (iPr) 2, Me3CO2CCH2Br, tetrahydrofuran; (v) LiBHEt3, tetrahydrofuran; subsequently Et3SiH, BF3"Et2O, dichloromethane; (vi) CF3CO2H, dichloromethane.

Methyl ester of 2-nitromethyl-cyclohexanecarboxylic acid (2) A solution of methyl ester of cyclohex-1-anocarboxylic acid 1 (5.15 g, 36.7 mmol), tetrabutylammonium fluoride (55.10 ml, 1 M in THF, 55.1 mmol) and nitromethane (3.97 ml, 73.5 mmol) in tetrahydrofuran (60 ml) was heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was diluted with diethyl ether (500 ml), washed with 2N HCl (2x100 ml) and subsequently with brine (2x100 ml). The phases separated. The organic phase was dried over MgSO and concentrated in vacuo. The crude mixture was purified by silica gel chromatography (EtOAc / heptane 1: 4) to give 2 (5.46 g, cis and trans-isomers: 73%) as a pale yellow liquid. 1 H NMR 2 (CDCl 3) d ppm: 1.1 to 2.4 (m, 10H); 3.7 (s, 3H); 4.25 (dd, 1 H); 4.45 (dd, 1H). MS ES + [MW + 1] +: 202.

Octahydro-isoindol-1-one (3) A solution of 2 (5.42 g, 27 mmol) and catalyst in nickel sponge (cat.) In methanol (100 ml) was stirred at 30 ° C for 4 hours under an atmosphere of hydrogen (70 psi).

The catalyst was filtered through a pad of celite and the filtrate was concentrated in vacuo. Recrystallization from the crude solid (ether / heptane) gave 3 (3.69 g, 26.5 mmol, 98%) as a white powder. 1 H NMR (CDCl 3) d ppm: 1.2 to 2.4 (m, 10H); 2.9 (d, 1 H); 3.35 (m, 1 H); 5.7 (bs, 1 H). MS ES + [MW + 1] +: 140.

Tert-butyl ester of 1-Oxo-octahydro-isoindol-2-carboxylic acid (4) A 3 (835 mg, 6 mmol) suspended in tetrahydrofuran (7 ml) was added successively, under an argon atmosphere, 4-dimethylaminopipridine (18.3 mg, 0.15 mmol), triethylamino (0.84 ml, 6 mmol) and BOC2O (2.62 g, 12 mmol). The reaction mixture was stirred at room temperature for 3 days. The solvent was removed in vacuo. The residue was diluted with diethyl ether (20 ml) and washed with water (2 x 10 ml). The phases were separated and the organic phase was dried over MgSO4 and concentrated. The crude oil was purified by silica gel chromatography (ether / heptane 1: 1) to give 4 (986 mg, 4.1 mmol, 70%) as a white solid. 1 H NMR (CDCl 3) d ppm: 1.2 to 2.6 (m, 10H); 1.5 (s, 9H); 3.4 (d, 1H); 3.6 (dd, 1 H). MS ES + [MW + 1] +: 240. [3aS- (3a7aa)] - 7a-tert-Butoxycarbonylmethyl-1-oxo-octahydro-isoindol-2-carboxylic acid tert-butyl ester (5) Lithium diisopropylamide was prepared by the dropwise addition of n-BuLi (1.39 ml, 2.5 M in hexanes, 3.47 mmol) was added to a stirred cooled solution (-10 ° C) of i-Pr2NH (0.63 ml, 4.5 mmol) in dry tetrahydrofuran (33 ml). 20 minutes.The mixture was cooled to -78 ° C and 4 (832 mg, 3.47 mmol), dissolved in dry tetrahydrofuran (2 ml), added for 5 minutes.After 30 additional minutes, érf-Butylbromoacetate was added dropwise. (0.77 mL, 5.21 mmol) The mixture was then warmed to room temperature, NN-dimethylpropyleneurea (5 mL, 41.3 mmol) was added and the reaction mixture was heated above 75 ° C for 5 hours. saturated NH4CI (10 mL) was added and the mixture was extracted with diethyl ether (2x20 mL) The phases were separated and the organic phase was dried over MgSO4 and concentrated The residue was purified by silica gel chromatography (ether / heptane 1: 1) to give 5 (840 mg, 2.37 mmol, 70%) as a colorless oil. 1 H NMR (CDCl 3) d ppm: 1.2 to 1.7 (m, 8H); 1.4 (s, 9H); 1.55 (s, 9H); 2.5 (m, 1 H); 2.55 [ABjq, 2H); 3.45 (dd, 1H); 3.75 (dd, 1H). MS ES + [Mw + 23] +: 376. [3aS- (a7aa)] - 3a-tert-Butoxycarbonylmethyl-octahydro-isoindol-2-carboxylic acid tert-butyl ester (6) To a cooled solution (-78 ° C) of 5 (340 mg, 0.96 mmol) in Dry tetrahydrofuran (6 ml) was added under an atmosphere of argon, LiBHEt3 (1.15 ml, 1 M in THF, 1.15 mmol). The reaction mixture was warmed after 4 hours by the addition of saturated aqueous NaHCO3 (1.8 ml). The mixture was warmed above 0 ° C. Thirty percent H2O2 (5 drops) was added and the mixture was stirred at 0 ° C for an additional 30 minutes. The solvent was subsequently removed in vacuo and the aqueous phase was extracted with CH2Cl2. (3x5 ml). The organic phases were combined, dried over MgSO4 and concentrated. To the crude residue in CH2Cl2 (15 ml) was added, at -78 ° C, under an atmosphere of argon, Et3SiH (0.15 ml, 0.96 mmol) and BF3 »Et2O (0.135 ml, 1.05 mmol). After stirring for 30 minutes, an additional amount of Et 3 SiH (0.15 ml, 0.96 mmol) and BF 3 »Et 2 O (0.135 ml, 1.05 mmol) was added and the reaction mixture was stirred at -78 ° C for 3 hours. Tempering was achieved at -78 ° C by the addition of saturated aqueous NaHCO3 (1.5 ml). The phases were separated and the organic phase was dried over MgSO and concentrated. The residue was purified by silica gel chromatography (Et 2 O / heptane 1: 1) to give 6 (157 mg, 0.46 mmol, 48%) as a colorless oil. 1 H NMR (CDCl 3) d ppm: 1.2 to 1.4 (m, 26H); 2 (m, 1H); 2.15 (d, 1H); 2.55 (dd, 1H); 3.2 to 3.5 (m, 4H).

MS ES + [MW + 1j +: 340. [3aS- (3a7aa)] - (Octahydro-isoindol-3a-yl) -acetic acid trifluoroacetate (7) A solution of 6 (100 mg, 0.29 mmol) in a mixture of CH2Cl2 / TFA (2 ml, 50:50) ) was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was diluted with water (2 ml) and washed with ether (2 × 2 ml). The phases were separated and the aqueous phase was concentrated in vacuo to give 7 (60 mg, 0.17 mmol, 69%) as a pale yellow gum. 1 H NMR (D 2 O) d ppm: 1.4 to 1.8 (m, 8H); 2.3 (m, 1H); 2.5 (d, 1 H); 2.95 (d, 1 H); 3.35 to 3.95 (m, 4H). MS ES + [MW + 1] +: 184. C, H, N, Cale, for C10H? 7NO2 »1.0C2HF3O2« 0.7H2O: C, 46.51; H, 6.31; N, 4.52. Observed: C, 46.48; H, 5.98; N, 4.57.

The following compounds can also be prepared by the above synthetic methods: 7-Methyl-2-aza-spiro [4.4] nonane-4-carboxylic acid; 7,8-Dimethyl-2-aza-spiro [4.4] nonane-4-carboxylic acid; 7-Methyl-2-aza-spiro [4.5] decane-4-carboxylic acid; 7,9-Dimethyl-2-aza-spiro [4.5] decane-4-carboxylic acid; Spiro [bicyclo [3.3.1] nonane-9,3 '-pyrrolodine] -4'-carboxylic acid; Spiro acid [pyrrolidine-3,2'-tricyclo [3.3. .13.7] decane] -4-carboxylic acid; 3-Amino-6-methyl-spiro [3.5] nonane-1-carboxylic acid; 3-Amino-6,8-dimethyl-spiro [3.5] nonane-1-carboxylic acid; 4-Amino-7-methyl-spiro [4.5] decane-1-carboxylic acid; 4-Amino-7,9-dimethyl-spiro [4,5-decane-1-carboxylic acid; 3-Amino-6-methyl-spiro [3,4] octane-1-carboxylic acid; 3-Amino-6,7-dimethyl-spiro [3,4] octane-1-carboxylic acid; 4-Amino-7-methyl-spiro [4.4] nonane-1-carboxylic acid and 4-Amino-7,8-dimethyl-spiro [4.4] nonane-1-carboxylic acid. s the above compounds, all stereocenters can be R or S. mplo: Mixture of 4 unproven isomers Chromatography separation Mixture of 2 isomers Mixture of 2 isomers! C5? =? or μM! C50 = 0.38, μM Chromatography separation Simple isomer Simple isomer 1C50 - 0.088 μM IC50 * = 0.946 μM

Claims (19)

1. A compound of the formula p III or a pharmaceutically acceptable salt or a prodrug thereof wherein R-α to R 10 are each independently selected from hydrogen or a long or branched chain alkyl of 1 to 6 carbon atoms, benzyl or phenyl; m is an integer from 0 to 3; n is an integer from 1 to 2; or is an integer from 0 to 3; p is an integer from 1 to 2; q is an integer from 0 to 2; r is an integer from 1 to 2; s is an integer from 1 to 3; t is an integer from 0 to 2 and u is an integer from 0 to 1.

2. A compound accor to claim 1 of Formula I.

A compound accor to claim 1 of Formula I, wherein Ri to Rio is hydrogen; m is from 0 to 3 and n is 1 or 2.

A compound accor to claim 1 selected from: (±) -2-Aza-spiro [3.5] nonane-1-carboxylic acid hydrochloride; (+) - 2-Aza-spiro [4,5-decane-4-carboxylic acid hydrochloride; (R) -2-Aza-spiro [4,5-decane-4-carboxylic acid hydrochloride; (S) -2-Aza-spiro [4.5] decane-4-carboxylic acid and (R) -2-Aza-spiro [4.5] decane-4-carboxylic acid hydrochloride.

A compound accor to claim 1 of Formula II.

A compound accor to claim 1 of Formula II, wherein Ri to Rio is hydrogen or is from 0 to 3 and p is 1 to 2.

A compound accor to claim 1 of Formula III, wherein Ri to R10 is hydrogen, q is from 0 to 2 and r is 1 to 2.

A compound accor to claim 1 of Formula III, wherein: (+) - [3aS- (3a, 7aa)] - (Octahydro-isoindol-3a-yl) -acetic acid trifluoroacetate.

A compound accor to claim 1 and selected from: 7-Methyl-2-aza-spiro [4.4] nonane-4-carboxylic acid; Acid [4a, 5β (R *)] 7-Methyl-2-aza-spiro [4.5] decane-4-carboxylic acid; Acid [4a, 5a (S *)] 7-Methyl-2-aza-spiro [4.5] decane-4-carboxylic acid; Acid [4a, 5a (R *)] 7-Methyl-2-aza-spiro [4.5] decane-4-carboxylic acid; Acid [4a, 5a (S *)] 7-Methyl-2-aza-spiro [4.5-decane-4-carboxylic acid; 7,8-Dimethyl-2-aza-spiro [4.4] nonane-4-carboxylic acid; 7-Methyl-2-aza-spiro [4,5-decane-4-carboxylic acid; 7,9-Dimethyl-2-aza-spiro [4.5] decane-4-carboxylic acid; Spiro [bicyclo [3.3.1] nonane-9,3'-pyrroli] -4'-carboxylic acid; Spiro [pyrroli-3,2'-tricyclo [3.3.1.13,7] decane] -4-carboxylic acid; 3-Amino-6-methyl-spiro [3.5] nonane-1-carboxylic acid; 3-Amino-6,8-dimethyl-spiro [3.5] nonane-carboxylic acid; 4-Amino-7-methyl-spiro [4.5] decane-1-carboxylic acid; 4-Amino-7,9-dimethyl-spiro [4.5] decane-1-carboxylic acid; 3-Amino-6-methyl-spiro [3,4] octane-1-carboxylic acid; 3-Amino-6,7-dimemethyl-spiro [3,4-joctane-1-carboxylic acid, 4-Amino-7-methyl-spiro [4.4] nonane-1-carboxylic acid and 4-Amino-7,8-dimethyl- spiro [4.4] nonane-1-carboxylic acid.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound accor to claim 1 and a pharmaceutically acceptable carrier.

11. A method for the treatment of epilepsy comprising administering a therapeutically effective amount of a compound accor to claim 1 to a mammal in need of said treatment.

12. A method for the treatment of mental gaps, hypokinesia and cranial diseases comprising the administration of a therapeutically effective amount of a compound accor to claim 1 to a mammal in need of said treatment.

13. A method for the treatment of neurodegenerative diseases comprising the administration of a therapeutically effective amount of a compound accor to claim 1 to a mammal in need of said treatment.

14. A method for the treatment of depression comprising the administration of a therapeutically effective amount of a compound accor to claim 1 to a mammal in need of said treatment.

15. A method for the treatment of anxiety comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of said treatment.

16. A method for the treatment of panic comprising the administration of a therapeutically effective amount of a compound in accordance with the claim 1 to a mammal in need of such treatment.

17. A method for pain treatment comprising administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of said treatment.

18. A method for the treatment of neuropathological diseases comprising the administration of a therapeutically effective amount of a compound according to claim 1 to a mammal in need of said treatment.

19. A compound selected from: 2-Benzyl-2-aza-spiro [4.5] decane-4,4-dicarboxylic acid dimethyl ester hydrochloride; 2-Aza-spiro [4.5] decane-4,4-dicarboxylic acid dimethyl ester hydrochloride; 1-Benzyloxymethyl-2-aza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester; 1-Hydroxymethyl-2-aza-spiro [3.5] nonane-2-carboxylic acid tert-butyl ester; 2-Aza-spiro [3.5] nonane-1,2-dicarboxylic acid 2-tert-butyl ester; Tert-butyl ester of [3aS (3a7aa)] - 7a-tert-Butoxycarbonylmethyl-1-oxo-octahydro-isoindol-2-carboxylic acid and [3aS (3a7aa)] - 3a-tert-Butoxycarbonylmethyl- tert -butyl ester octahydro-isoindol-2-carboxylic acid.